The present invention relates to bicyclic heterocycles of general formula 
the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R2 denotes a hydrogen or fluorine atom,
one of the groups Rb or Rc denotes an R3xe2x80x94(CH2)mxe2x80x94O group and the other group Rb or Rc denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R3 denotes an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group, an R4xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Nxe2x80x94CH2CH2xe2x80x94OH group substituted at the methylene groups by one or two methyl or ethyl groups, wherein
R4 represents a hydrogen atom or a C1-4-alkyl group,
or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and
m denotes the number 2, 3 or 4,
with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline and
4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-thoxy}-7-methoxy-quinazoline
are excluded,
the tautomers, the stereoisomers and the salts thereof.
Preferred compounds of the above general formula I are those wherein
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and R2 denotes a hydrogen or fluorine atom,
one of the groups Rb or Rc denotes a R3xe2x80x94(CH2)mxe2x80x94O group and the other group Rb or Rc denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R3 denotes an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group,
an R4xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Nxe2x80x94CH2CH2xe2x80x94OH group substituted at the methylene groups by one or two methyl or ethyl groups wherein
R4 represents a hydrogen atom or a C1-4-alkyl group,
or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and
m represents the number 2, 3 or 4,
with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(3-methyl-2-oxo-morpholin-4-yl)ethoxy)-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(5, 5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline,
(R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and
(R)4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline
are excluded,
particularly those wherein
Ra represents a 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 represents a fluorine, chlorine or bromine atom, a methyl or ethynyl group and R2 denotes a hydrogen or fluorine atom,
one of the groups Rb or Rc represents a R3xe2x80x94(CH2)mxe2x80x94O group and the other group Rb or Rc represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R3 represents an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino group, an R4xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Nxe2x80x94CH2CH2xe2x80x94OH group substituted at the methylene groups by one or two methyl groups, wherein
R4 represents a C1-4-alkyl group,
or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and
m represents the number 2, 3 or 4,
with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(3-methyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{ 2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline,
(R)4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and
(R)4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline
are excluded,
the tautomers, the stereoisomers and the salts thereof.
Particularly preferred compounds of general formula I are those wherein
Ra represents a 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 denotes a fluorine, chlorine or bromine atom and R2 denotes a hydrogen or fluorine atom,
one of the groups Rb or Rc denotes a R3xe2x80x94(CH2)mxe2x80x94O group and the other group Rb or Rc denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R3 denotes an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino group or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and
m represents the number 2, 3 or 4,
with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(3-methyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline,
(R)4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinzoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and
(R)4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline
are excluded,
the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds of general formula I are those wherein
Ra denotes a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,
Rb denotes a R3xe2x80x94(CH2)mxe2x80x94O group, wherein
R3 denotes a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and
m denotes the number 2 or 3,
and Rc denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, with the proviso that the compounds
4-[(3-bromo-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(3-methyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline and
(R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline
are excluded,
the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds of general formula I are also those wherein
Ra denotes a 3-chloro-4-fluorophenyl group,
Rb denotes a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group and
Rc denotes a R3xe2x80x94(CH2)mxe2x80x94O group, wherein
R3 denotes a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and
m denotes the number 2,
with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline and
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,
are excluded,
the tautomers, the stereoisomers and the salts thereof.
The following are mentioned by way of example as most particularly preferred compounds:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
(2) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-quinazoline,
(3) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
(4) 4-[(3-chloro-4-fluorophenyl)amino1-7-cyclobutyloxy-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-quinazoline,
(5) 4-(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-quinazoline,
(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-quinazoline,
(7) 4-[(3-bromo-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
(8) 4-[(3-bromo-phenyl)amino]-6-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
(9) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
(10) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-((R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,
(11) 4-[(R)-(1-phenyl-ethyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,
(12) 4-[(R)-(1-phenyl-ethyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-ethoxy-quinazoline and
(13) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
the tautomers, the stereoisomers and the salts thereof.
The compounds of general formula I may be prepared by the following methods, for example:
a) reacting a compound of general formula 
xe2x80x83wherein
Ra is as hereinbefore defined,
one of the groups Rbxe2x80x2 or Rcxe2x80x2 represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and the other group Rbxe2x80x2 or Rcxe2x80x2 represents a Z1xe2x80x94(CH2)mxe2x80x94O group, wherein
m is as hereinbefore defined and
Z1 denotes a leaving group such as a halogen atom or a sulphonyloxy group such as a chlorine or bromine atom, a methanesulphonyloxy or p-toluenesulphonyloxy group,
with a compound of general formula
xe2x80x83Hxe2x80x94R3xe2x80x83xe2x80x83,(III)
xe2x80x83wherein
R3 is as hereinbefore defined.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine, whilst these organic bases may simultaneously also act as solvent, or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, expediently at temperatures between xe2x88x9220 and 200xc2x0 C., preferably at temperatures between 0 and 150xc2x0 C.
b) cyclising a compound of general formula 
xe2x80x83optionally formed in the reaction mixture
xe2x80x83wherein
Ra is as hereinbefore defined,
one of the groups Rbxe2x80x3 or Rcxe2x80x3 represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and the other group Rbxe2x80x3 or Rcxe2x80x3 represents a R3xe2x80x2xe2x80x94(CH2)mxe2x80x94O group, wherein
m is as hereinbefore defined and
R3xe2x80x2 denotes a R4xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Nxe2x80x94CH2CH2xe2x80x94OH group substituted at the methylene groups by one or two methyl or ethyl groups, wherein
R4 represents a hydrogen atom or a C1-4-alkyl group.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethyl sulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, expediently in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulphonic acid or sulphuric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexyl-carbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and
protecting groups for an imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120xc2x0 C., preferably at temperatures between 10 and 100xc2x0 C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100xc2x0 C., but preferably at ambient temperatures between 20 and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxan, methanol or diethyl ether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120xc2x0 C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50xc2x0 C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
In addition, if the new compounds of formula I thus obtained contain a carboxy, hydroxyphosphoryl, sulpho or 5-tetrazolyl group, they may, if desired, subsequently be converted into the salts thereof with inorganic or organic bases, particularly, for pharmaceutical use, into the physiologically acceptable salts thereof. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae II to IV used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. Examples I to XIV).
As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible that the transmission of signals to components located further down is blocked.
The biological properties of the new compounds were investigated as follows:
The inhibition of the EGF-R-mediated signal transmission can be demonstrated e.g. with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. A cell line of murine origin dependent on interleukin-3-(IL-3) which was genetically modified to express functional human EGF-R was used here. The proliferation of these cells known as F/L-HERc can therefore be stimulated either by murine IL-3 or by EGF (cf. von Rxc3xcden, T. et al. in EMBO J. 7, 2749-2756 (1988) and Pierce, J. H. et al. in Science 239, 628-631 (1988)).
The starting material used for the F/L-HERc cells was the cell line FDC-P1, the production of which has been described by Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth-factor-dependent cells may also be used (cf. for example Pierce, J. H. et al. in Science 239, 628-631 (1988), Shibuya, H. et al. in Cell 70, 57-67 (1992) and Alexander, W. S. et al. in EMBO J. 10, 3683-3691 (1991)). For expressing the human EGF-R cDNA (cf. Ullrich, A. et al. in Nature 309, 418-425 (1984)) recombinant retroviruses were used as described by von Rxc3xcden, T. et al., EMBO J. 7, 2749-2756 (1988), except that the retroviral vector LXSN (cf. Miller, A. D. et al. in BioTechniques 7, 980-990 (1989)) was used for the expression of the EGF-R cDNA and the line GP+E86 (cf. Markowitz, D. et al. in J. Virol. 62, 1120-1124 (1988)) was used as the packaging cell.
The test was performed as follows:
F/L-HERc cells were cultivated in RPMI/1640 medium (BioWhittaker), supplemented with 10% foetal calf serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng/ml of human EGF (Promega), at 37xc2x0 C. and 5% CO2. In order to investigate the inhibitory activity of the compounds according to the invention, 1.5xc3x97104 cells per well were cultivated in triplicate in 96-well dishes in the above medium (200 xcexcl), the cell proliferation being stimulated with either EGF (20 ng/ml) or murine IL-3. The IL-3 used was obtained from culture supernatants of the cell line X63/0 mIL-3 (cf. Karasuyama, H. et al. in Eur. J. Immunol. 18, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethylsulphoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37xc2x0 C.
In order to determine the inhibitory activity of the compounds according to the invention the relative cell number was measured in O.D. units using the Cell Titer 96(trademark) AQueous Non-Radioactive Cell Proliferation Assay (Promega). The relative cell number was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was derived therefrom. The following results were obtained:
The compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. These are e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, xcex11-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn""s disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Mxc3xa9nxc3xa9trier""s disease, secreting adenomas and protein loss syndrome, and also for treating nasal polyps and polyps of the gastrointestinal tract of various origins such as villous or adenomatous polyps of the large intestine, but also polyps in familial polyposis coli, in intestinal polyps in Gardner""s syndrome, in polyps throughout the entire gastro-intestinal tract in Peutz-Jeghers Syndrome, in inflammatory pseudopolyps, in juvenile polyps, in colitis cystica profunda and in pneumatosis cystoides intestinales.
In addition, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat kidney diseases, particularly in cystic changes as in cystic kidneys, for treating renal cysts which may be idiopathic in origin or occur in syndromes such as tubercular sclerosis, in von Hippel-Lindau syndrome, in nephrophthisis and spongy kidney and other diseases caused by abnormal function of tyrosine kinases, such as e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, etc.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), compounds which interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti-inflammatory activity. For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion, or anti-inflammatory substances. These combinations may be administered either simultaneously or sequentially.
These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.